Magnetic resonance imaging (MRI) of metabolic markers offers a powerful method to screen and diagnose diseases as well as to gauge response to treatment. Yet at Boltzmann equilibrium, spin polarizations of conventional MR (on the order of ˜10−5-10−6) are too low, and the metabolites are often too dilute, to detect, quantify, or image such substances in vivo on a reasonable time-scale. However, spin order attained by ‘hyperpolarizing’ substances beyond Boltzmann levels can be high enough to overcome such otherwise-poor detection sensitivity. Because the high nuclear spin polarization is independent of magnetic field, strong magnetic fields are unnecessary for some applications, permitting low/zero-field MRS/MRI, and even remotely-detected MRS/MRI.
Known hyperpolarization techniques include dynamic nuclear polarization (DNP) and Optical Pumping; however, another route to address the NMR/MRI sensitivity problem is to use parahydrogen (pH2) as the hyperpolarization source, as is done in a family of techniques referred to collectively as Parahydrogen-Induced Polarization (PHIP). In traditional PHIP, molecular precursors with unsaturated chemical bonds are hydrogenated via molecular addition of pH2, thereby transferring the nuclear spin order to the molecular products. In a more recent variant, referred to as Signal Amplification by Reversible Exchange (SABRE), spin order may be transferred from pH2 to target molecules during the lifetime of transient molecular complexes without permanent chemical change.
Signal Amplification by Reversible Exchange (SABRE) generally uses an organometallic catalyst to transiently co-locate pH2 and the target substrate molecule in a low-symmetry complex in solution. In low field, net spin order can be transferred from the pH2 to the spins of the substrate via scalar couplings. Crabtree's catalyst ([Ir(COD)(PCy3)(Py)][PF6]), where Cy is cyclohexyl and COD is cyclooctadiene, has previously yielded ˜5-100-fold enhancements in pyridine, and has been used to achieve substantial enhancements at low field (e.g., of amino acids). N-heterocyclic carbene (NHC) iridium complex (with NHC: 1,3-bis(2,4,6-trimethylphenyl)-imidazole-2-ylidine, “IMes”) has been used to yield polarization enhancements up to ˜8100-fold of pyridine at 3 T, with subsequent results reported for biomedically-relevant molecules in biologically tolerable organic solvents. Nevertheless, in order to broaden the applicability of SABRE, there exists a need for catalysts that can generate high spin polarization in aqueous substances. Despite the improved enhancements provided by the NHC-iridium complex, the complex and many of its derivatives are generally poorly soluble in water, potentially limiting biological/biomedical NMR/MRI experiments and applications.
In addition, achieving efficient hyperpolarization via SABRE has been generally limited to protons; while in some cases the resulting 1H polarization values were relatively high (e.g., P≈8%), such nonequilibrium polarization is relatively short-lived (T1 of seconds). Recent approaches to extend SABRE to longer-lived (T1≈1 min)15N hyperpolarization include LIGHT-SABRE (Low-Irradiation Generation of High Tesla-SABRE) and SABRE-SHEATH (SABRE in SHield Enables Alignment Transfer to Heteronuclei) using RF irradiation based and field-cycling-based approaches, respectively. SABRE-SHEATH is an advantageous approach because it only requires that the exchange reaction with para-H2 be performed in a microTesla field. 15N polarization levels of up to 10% have been shown. However, such hyperpolarization was achieved in dilute (4-45 mM) alcohol solutions with limited biocompatibility.